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Background: The immunocompetence handicap hypothesis suggests that males with a higher testosterone level should be better at developing male secondary traits, but at a cost of suppressed immune performance. As a result, we should expect that males with an increased testosterone level also possess a higher parasite load. However, previous empirical studies aimed to test this prediction have generated mixed results. Meanwhile, the effect of testosterone level on parasite load in female hosts remains poorly known., Methods: In this study, we tested this prediction by manipulating testosterone level in Daurian ground squirrels (Spermophilus dauricus), a medium-sized rodent widely distributed in northeast Asia. S. dauricus is an important host of ticks and fleas and often viewed as a considerable reservoir of plague. Live-trapped S. dauricus were injected with either tea oil (control group) or testosterone (treatment group) and then released. A total of 10 days later, the rodents were recaptured and checked for ectoparasites. Fecal samples were also collected to measure testosterone level of each individual., Results: We found that testosterone manipulation and sex of hosts interacted to affect tick load. At the end of the experiment, male squirrels subjected to testosterone implantation had an averagely higher tick load than males from the control group. However, this pattern was not found in females. Moreover, testosterone manipulation did not significantly affect flea load in S. dauricus., Conclusions: Our results only lent limited support for the immunocompetence handicap hypothesis, suggesting that the role of testosterone on regulating parasite load is relatively complex, and may largely depend on parasite type and gender of hosts., (© 2024. The Author(s).)

Background: Usutu virus (USUV) is an emerging neurotropic arthropod-borne virus recently involved in massive die offs of wild birds predominantly reported in Europe. Although primarily asymptomatic or presenting mild clinical signs, humans infected by USUV can develop neuroinvasive pathologies (including encephalitis and meningoencephalitis). Similar to other flaviviruses, such as West Nile virus, USUV is capable of reaching the central nervous system. However, the neuropathogenesis of USUV is still poorly understood, and the virulence of the specific USUV lineages is currently unknown. One of the major complexities of the study of USUV pathogenesis is the presence of a great diversity of lineages circulating at the same time and in the same location., Methods: The aim of this work was to determine the neurovirulence of isolates from the six main lineages circulating in Europe using mouse model and several neuronal cell lines (neurons, microglia, pericytes, brain endothelial cells, astrocytes, and in vitro Blood-Brain Barrier model)., Results: Our results indicate that all strains are neurotropic but have different virulence profiles. The Europe 2 strain, previously described as being involved in several clinical cases, induced the shortest survival time and highest mortality in vivo and appeared to be more virulent and persistent in microglial, astrocytes, and brain endothelial cells, while also inducing an atypical cytopathic effect. Moreover, an amino acid substitution (D3425E) was specifically identified in the RNA-dependent RNA polymerase domain of the NS5 protein of this lineage., Conclusions: Altogether, these data show a broad neurotropism for USUV in the central nervous system with lineage-dependent virulence. Our results will help to better understand the biological and epidemiological diversity of USUV infection.

Reproduction is energetically expensive and investing in this life history trait is likely accompanied by significant changes in physiological activity. Investment strategy necessary for achieving reproductive success in reptiles can vary with reproductive form and pattern, potentiating different consequences for competing fitness-related traits such as those key to survival. The goal of this study was to assess if and how energetic state (i.e., energy metabolites) and self-maintenance (i.e., immunocompetence) are hormonally modulated across reproductive contexts in an oviparous, parthenogenetic lizard, the Colorado Checkered Whiptail Aspidoscelis neotesselata. Here blood plasma samples were collected from lizards within the US Army Fort Carson Military Installation near Colorado Springs, CO, USA, during seasons of reproductive activity (i.e., June) and inactivity (i.e., August). Measures of reproductive (i.e., estradiol) and energy-mobilizing (i.e., corticosterone) hormones, energy metabolites (i.e., glucose, triglycerides, and free glycerol), and innate immunity (i.e., bactericidal ability) were compared by season and reproductive stage. Levels of energy metabolites and bactericidal ability were compared to levels of E 2 and CORT. Bactericidal ability was also compared to levels of energy metabolites. Corticosterone and glucose levels were lower during the reproductive season while triglyceride levels and bactericidal ability were higher, but both estradiol and free glycerol levels did not differ between seasons. Throughout vitellogenesis, corticosterone and glucose levels as well as bactericidal ability did not differ, but estradiol levels were higher during early and mid-stage and both triglyceride and free glycerol levels were lower during gravidity. Corticosterone levels were negatively associated with circulating triglycerides and bactericidal ability, but were not related to glucose nor free glycerol levels. Estradiol levels were positively associated with free glycerol levels and bactericidal ability, but were not related to glucose nor triglyceride levels. Finally, bactericidal ability was negatively associated with glucose, but positively associated with triglycerides. Differences in energetic state and immunocompetence are thus reflected by shifts in hormone secretion across reproductive investment. These findings provide partial support for the hypothesis that energetic state is differentially regulated by steroid hormones to afford reproduction, potentially at the cost of future survival., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cancer has traditionally been treated with surgery, cytotoxic chemotherapy and/or radiotherapy. The focus of treatment has been the mutated neoplastic cell. Critical advances in genomic and molecular techniques herald the potential for personalized treatments. Incremental breakthroughs in immunology have translated to a step-change in care by providing a mechanistic understanding of the immune system and how it may be mobilized to target cancer cells. As a result, clinical trials of immune-modifying agents have increased at an exponential rate and are revolutionizing cancer care. It is increasingly likely that the surgical oncologist will find themself caring for patients who have had immuno-oncology therapies as part of their neoadjuvant or adjuvant treatment. This review provides an update on immuno-oncology for the surgeon, covering the mechanisms of action of the agents in use. Emerging and surgically relevant toxicities are discussed, and available data on combining and sequencing cancer surgery with immuno-oncology treatments are summarized., (© 2019 BJS Society Ltd Published by John Wiley & Sons Ltd.)

The gender differences of immunity have been elucidated in many vertebrates and invertebrates. However, the information of this difference was still not clear in the sea cucumber Apostichopus japonicus, which is one of the most valuable aquaculture species and susceptible to diseases caused by pathogen infection. In the present study, the transcriptome of coelomocytes from female and male A. japonicus before and after spawning was obtained by RNA-sequencing technology. A total of 4,538 and 8,248 differentially expressed genes were identified between female and male A. japonicus before and after spawning, respectively, indicating that the gender differences of gene expression profiles in A. japonicus were more remarkable after spawning. Further KEGG enrichment analyses were conducted for both male and female up-regulated genes before and after spawning. The results revealed that the capacity to kill pathogens in female A. japonicus might be more powerful than that in males no matter before and after spawning; the antioxidant ability in male A. japonicus was probably stronger than that in females after spawning; the complement system in male A. japonicus might be more effective than that in females after spawning; and the apoptosis was likely to be more serious in male A. japonicus before spawning. Moreover, we speculated that the fatty acid composition might be one of the inducements for gender specific immune differences of A. japonicus. Overall, the results of our study illustrated the global gender specific immune differences of A. japonicus and contributed to understanding of the molecular mechanisms underlying sea cucumber immune regulation., (Copyright © 2019. Published by Elsevier Ltd.)

Intracranial fungal infection of the cavernous sinus is a condition that usually affects immunocompromised individuals and is rarely seen in immunocompetent individuals. It is a potentially life threatening condition which requires prompt treatment. Here we present a case of an immunocompetent patient with a fungal infection of the cavernous sinus.

Cryptococcal meningitis is an opportunistic infection predominantly affecting immunocompromised patients but rarely can affect the immunocompetent. We describe a 53-year-old Caucasian man who presented complaining of a 2-week history of severe bilateral eye pain and diplopia. His only known risk factor was that he lived in a horse farm and recently shot bats and pigeons in his barn. He visited an outside hospital during this time without a diagnosis established. After further deliberation, we obtained a lumbar puncture (LP) which revealed an opening pressure (OP) of 27 cm H 2 O. Cerebrospinal fluid (CSF) and fungal cultures confirmed the presence of Cryptococcus neoformans The patient was diagnosed with C. neoformans- mediated meningoencephalitis and was initiated on the appropriate induction anti-fungal therapy. This case emphasises the need for clinicians to remain vigilant and consider cryptococcal meningitis in immunocompetent individuals even when classic symptoms of meningitis are absent., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Recent studies have called into question the idea that facial masculinity is a condition-dependent male ornament that indicates immunocompetence in humans. We add to this growing body of research by calculating an objective measure of facial masculinity/femininity using 3D images in a large sample ( n = 1,233) of people of European ancestry. We show that facial masculinity is positively correlated with adult height in both males and females. However, facial masculinity scales with growth similarly in males and females, suggesting that facial masculinity is not exclusively a male ornament, as male ornaments are typically more sensitive to growth in males compared with females. Additionally, we measured immunocompetence via heterozygosity at the major histocompatibility complex (MHC), a widely-used genetic marker of immunity. We show that, while height is positively correlated with MHC heterozygosity, facial masculinity is not. Thus, facial masculinity does not reflect immunocompetence measured by MHC heterozygosity in humans. Overall, we find no support for the idea that facial masculinity is a condition-dependent male ornament that has evolved to indicate immunocompetence., Competing Interests: The authors declare no conflict of interest.

Objectives: More symmetric organisms are perceived as more attractive. Fluctuating asymmetry (FA) i.e. small, random deviations from perfect bilateral symmetry, is supposed to inform about developmental instability. According to the good genes hypothesis, a low level of FA is a putative cue to an organism's biological quality. An important aspect of this quality is the immune system functioning. The aim of this study was to evaluate the relationship between immune system functioning and body symmetry in healthy people., Materials and Methods: The composite body FA (cFA) was assessed on the basis of six bilateral traits (on hands and feet). The ISF was determined by many innate (total complement and lysozyme activity, neutrophils function) and adaptive immune parameters (T CD3 and B CD19 lymphocytes, total IgA and IgG and response to flu vaccine). A total of 98 men and 92 women were subjected to flu (among them 37 men and 30 women also to tetanus) vaccination. The blood samples were collected before and 4 weeks after the antigens exposure. Immunomodulatory factors: participant's age, body fat, and free testosterone level, were controlled., Results: Apart from the weak positive association between CD3 or CD19 and cFA in men, we found no association between the level of body symmetry and the rest of the analyzed immune parameters for both sexes., Discussion: Our results are the opposite of the good genes hypothesis prediction and suggest that in western, healthy populations, human mate preferences for more symmetric bodies are not related to immune competence., (© 2018 Wiley Periodicals, Inc.)

The immunocompetence handicap hypothesis (ICHH) proposes that testosterone has both beneficial effects on male reproductive potential and negative effects by suppressing the immune system. However, support for the ICHH has been variable and an alternative hypothesis suggests that testosterone may be acting indirectly via cortisol to suppress immunity (the stress-linked ICHH). A third hypothesis is that increased energetic investment in immunity results in the suppression of testosterone. We tested these hypotheses in male Cape ground squirrels ( Xerus inauris ) through two separate manipulations: first, by triggering a strong immune response using a lipopolysaccharide (LPS) injection and, secondly, by increasing circulating testosterone using silastic testosterone implants. Responding to an immune challenge significantly reduced testosterone, supporting the immune suppression hypothesis, while increasing circulating testosterone had no effect on immunocompetence, body mass, ectoparasite abundances or cortisol levels, failing to support either the ICHH or stress-linked ICHH. Our results add to the increasing body of literature that challenges the ICHH, and we conclude that the trade-off between testosterone and immunity is mediated through immune activation and not through testosterone in male Cape ground squirrels. Being able to test the ICHH, stress-linked ICHH and immune suppression hypotheses in a free-ranging mammal gives us a unique opportunity to examine the mechanisms mediating this trade-off., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

A previously healthy 67-year-old farmer presented to an outside hospital after a 2-week history of non-specific respiratory symptoms. A certain diagnosis was not initially apparent, and the patient was discharged home on a regimen for presumed chronic obstructive pulmonary disease exacerbation. He re-presented to the emergency department with shock and hypoxaemic respiratory failure requiring prompt intubation and fluid resuscitation. He was then transferred to our institution due to multiorgan failure. On arrival, the patient demonstrated refractory shock and worsening acute kidney injury, severe anaemia and thrombocytopaenia. The peripheral smear revealed absence of microangiopathic haemolytic anaemia. A closer review of the smear displayed red blood cell inclusion bodies consistent with babesiosis. The patient was started on clindamycin and loaded with intravenous quinidine, and subsequently transitioned to oral quinine. A red cell exchange transfusion was pursued with improvement of the parasite load. The patient was discharged home on clindamycin/quinine and scheduled for outpatient intermittent haemodialysis., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Younger patients with colorectal cancer (CRC) generally have better survival in spite of worse clinical and pathological features., Methods: Twenty-six patients under 50 years operated for primary CRC were enrolled and matched 1:2:2 according to stage, tumor site and gender with 52 patients from 50 to 70 years and 52 patients over 70 years old., Results: Patients under 50 years had a significantly longer overall, cancer specific and disease free survival (p = .001, p = .007 and p = .05, respectively). However, they had more frequently lymphovascular invasion (p = .006) and they more frequently developed metachronous CRC at follow-up (p = .03). Nevertheless, preoperative lymphocytes blood count/white blood count (LBC/WBC) ratio inversely correlated with age at operation (rho = -.21, p = .04) and it predicted CRC recurrence with an accuracy of 70%, p < .001 (threshold value LBC/WBC = 0.21%) and better overall, cancer specific and disease free survival (p < .0001 for all). At multivariate analysis, stage and LBC/WBC ratio resulted independent predictors of disease free survival (p = .0001 and p = .01, respectively)., Conclusions: Patients under 50 years had a significantly longer survival with a higher LBC/WBC ratio. These results could suggest a possible role of immunosurveillance in neoplastic control.

Repetitive administration is routinely used to maintain therapeutic drug levels, but previous studies have documented an accelerated blood clearance of some lipid-based delivery systems under these conditions. To assess the effect of repetitive administration, non-PEGylated lipoplexes (+/-0.5) were administered 4 times via tail vein injection at 3-day intervals to immunocompetent BALB/c mice bearing 4T1 tumors. This study measured the effect of repeat administration of nontargeted lipoplexes on clearance, cytokine/chemokine response, plasmid distribution, reporter gene expression, and liver toxicity. We do not observe a refractory period or a statistically significant difference in blood clearance between the first administration and subsequent injections of this lipoplex formulation, consistent with the absence of a cytokine/chemokine response. However, we do see a significant effect on both plasmid accumulation and expression, an enhancement of 26-fold and 10-fold in tumor plasmid levels and expression, respectively, after 4 injections as compared to that after a single injection. In addition, in vivo imaging suggests that expression in other organs had diminished rapidly 72 h after each administration, in contrast to relatively constant expression in the tumor. Taken together, the findings indicate that gene delivery to tumors can be dramatically enhanced by employing repetitive administration., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Dietary antioxidants have been shown to confer a variety of benefits through their ability to counter oxidative stress, including increased immunocompetence and reduced susceptibility to both infectious and non-infectious diseases. However, little is known about the effects of dietary antioxidants on immune function in larval amphibians, a group experiencing worldwide declines driven by factors that likely involve altered immunocompetence. We investigated the effects of dietary antioxidants (quercetin, vitamin E, and β-carotene) on two components of the immune system, as well as development and growth. Lithobates pipiens tadpoles fed diets with supplemental β-carotene or vitamin E exhibited an enhanced swelling response as measured with a phytohemagglutinin assay (PHA), but there was no induced antibody response. Effects were often dose-dependent, with higher antioxidant levels generally conferring stronger swelling that possibly corresponds to the innate immune response. Our results indicate that the antioxidant content of the larval amphibian diets not only had a detectable effect on their immune response capability, but also promoted tadpole growth (mass gain), although developmental stage was not affected. Given that many environmental perturbations may cause oxidative stress or reduce immunocompetence, it is critical to understand how nutrition may counter these effects., (Copyright © 2016 Elsevier Inc. All rights reserved.)

During the breeding season, male anuran amphibians produce advertisement calls. Androgens play a permissive role in the activation of calling activity, which is often positively correlated to androgen plasma levels and testes mass. Additionally, calling effort is also correlated to corticosterone plasma levels (hereinafter referred to as CORT), which is associated with the mobilization of energy substrates to sustain the high energy flux associated with this activity. However, high CORT also has many immunosuppressive effects and might interfere with reproduction. Consequently, CORT might mediate a compromise between reproductive effort and immunocompetence in anurans. In the present study, we investigated the relationship between calling rate, immunocompetence, and CORT in Hypsiboas albopunctatus, a midsize anuran occurring in South America. To understand these relationships, we conducted focal observations of calling behavior, followed by blood collection for CORT measurements and evaluation of some immune parameters. Our results showed that individuals with larger testes had higher calling rates, and those with higher calling rates showed lower cell-mediated immune response (swelling response to phytohaemagglutinin), although these relationships were not mediated by CORT. Furthermore, males calling early in the evening showed high CORT, and individuals with lower body condition index had higher CORT. We conclude that calling activity shows a cost in terms of cellular immune response in H. albopunctatus, but this compromise does not appear to be mediated by glucocorticoid plasma levels., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Lymphocyte exhaustion was recently recognized as a mechanism of immunosuppression in sepsis. While B cells are known to play pivotal roles in bacterial infection and sepsis, changes in B-cell-mediated humoral immunity have not been evaluated in critically ill septic patients. We aimed to investigate changes in humoral immunity caused by defective B-cell function during severe sepsis. Thirty-three severe sepsis patients and 44 healthy subjects were prospectively enrolled. Blood was collected from patients within 72 h of and 8 to 11 h after sepsis onset to measure B-cell subtypes, serum immunoglobulin M concentration, and CpG-B oligodeoxynucleotide-induced immunoglobulin M (IgM) production ex vivo. Participants were divided into two age groups: adults (18-64 years) and elderly (≥65 years). The fraction of CD21 exhausted B cells in acute sepsis patients (3.18%) was higher than that observed in healthy donors (0.77%, respectively, P <0.01). Significantly, serum IgM in elderly septic patients (≥65 years) was negatively correlated with acute physiology and chronic health evaluation II score (r = -0.57, P <0.05). Consistently, in B cells stimulated ex vivo, both aging and sepsis induced significant reductions in supernatant IgM (P <0.01). This finding was clinically relevant, as elderly patients with decreased IgM production might be more susceptible to infection by Gram-negative bacteria and fungi. Reduced immunocompetent B cells may be related to increased secondary infection after sepsis, especially in the elderly. Finally, impaired humoral immunity with increased CD21 exhausted B cells and insufficient immunoglobulin M production may be a critical immunological change in sepsis.

Purpose: To evaluate the usefulness of the secretion of interferon-γ (IFNγ) by cytomegalovirus (CMV)-specific CD8+ T cells to determine the risk of CMV reactivation in critically ill non-immunosuppressed patients., Methods: Two-center prospective cohort study including critically ill non-immunosuppressed CMV-seropositive patients admitted between December 2012 and March 2013. The incidence of CMV reactivation by polymerase chain reaction (real-time PCR) in plasma was investigated. IFNγ secretion by CMV-specific CD8+ T lymphocytes was determined at the time of admission to the intensive care unit (ICU) by means of the QuantiFERON(®)-CMV (QF-CMV) test. Cox regression analyses were performed to investigate CMV reactivation risk factors., Results: Fifty-three patients were included, of whom 13 (24.5%) presented CMV reactivation. Twenty-six patients (49.1%) were QF-CMV "reactive" (QF-CMV(R)). Of the 26 QF-CMV(R) patients, 11.5% (3/26) had CMV reactivation, whereas 37% (10/27) of QF-CMV "non reactive" patients (QF-CMV(NR)) presented reactivation (p = 0.03). By Cox regression, the presence of QF-CMV(R) at ICU admission (HR 0.09, 95% CI 0.02-0.44; p = 0.003) was associated with a decreased risk of CMV reactivation. The sensitivity, specificity, positive predictive value, and negative predictive value of QF-CMV were 77, 57, 37, and 88%, respectively. Eleven of the 53 patients (20.7%) died during the follow-up period. Mortality was more frequent in patients with CMV reactivation (6/13, 46.1 vs. 5/40, 12.5%; p = 0.015)., Conclusions: In critically ill non-immunosuppressed patients, the presence of functional CMV-specific CD8+ T lymphocyte response at intensive care unit admission provides protection against CMV reactivation.

Paracoccidioidomycosis and histoplasmosis are systemic fungal infections endemic in Brazil. Disseminated clinical forms are uncommon in immunocompetent individuals. We describe two HIV-negative patients with disseminated fungal infections, paracoccidioidomycosis and histoplasmosis, who were diagnosed by biopsies of suprarenal lesions. Both were treated for a prolonged period with oral antifungal agents, and both showed favorable outcomes.

Immunological competence declines progressively with age, resulting in increased susceptibility of the elderly to infection and impaired responses to vaccines. Underlying mechanisms remain largely obscure as they have been related to complex, individual systemic immune properties that are challenging to investigate. In this study, we explored age-related changes in human immunity during a primary virus infection experimentally induced by immunization with live-attenuated yellow fever (YF) vaccine. Applying detailed serology, advanced FACS analysis, and systems biology, we discovered that aged subjects developed fewer neutralizing Abs, mounted diminished YF-specific CD8(+) T cell responses, and showed quantitatively and qualitatively altered YF-specific CD4(+) T cell immunity. Among numerous immune signatures, low in vivo numbers of naive CD4(+) recent thymic emigrants and peripheral dendritic cells correlated well with reduced acute responsiveness and altered long-term persistence of human cellular immunity to YF vaccination. Hence, we reveal in this article that essential elements of immune responses such as recent thymic emigrants and dendritic cells strongly relate to productive immunity in the elderly, providing a conceivable explanation for diminished responsiveness to vaccination with neoantigens and infection with de novo pathogens in the aged population., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Testicular cell transplantation has generally been performed by using immune-deficient recipient mice to investigate the biology of spermatogonial stem cells (SSCs), the production of transgenic animals, and restoration of fertility. Recently, we demonstrated that rat spermatogenesis can occur in the seminiferous tubules of immune-competent recipient mice via pretreatment with busulfan (Myleran, 1, 4-butanediol methanesulfonate, 40 mg/kg) after transplantation of rat SSCs. However, considering the immunosuppressive effect of busulfan, there is a possibility that busulfan itself causes immune suppression in immune-competent recipient mice. The aim of this study was to determine the effects of busulfan on the immune system and spermatogenesis in immune-competent recipient mice. The results showed that at 60 days after busulfan treatment, just the same time as the transplantation, the recovery could be seen in the immune system including cell counts and functions of T and B lymphocytes in the spleen, but the spermatogenesis was more compromised. This study demonstrated that after busulfan pretreatment the immune system in immune-competent recipient mice had recovered by the time that rat spermatogenesis could occur in the murine testis. It became clear that xenogenic spermatogenesis can be tolerated in seminiferous tubules in the testes of immune-competent mice.

Gut immunocompetence involves immune, stress and regenerative processes. To investigate the determinants underlying inter-individual variation in gut immunocompetence, we perform enteric infection of 140 Drosophila lines with the entomopathogenic bacterium Pseudomonas entomophila and observe extensive variation in survival. Using genome-wide association analysis, we identify several novel immune modulators. Transcriptional profiling further shows that the intestinal molecular state differs between resistant and susceptible lines, already before infection, with one transcriptional module involving genes linked to reactive oxygen species (ROS) metabolism contributing to this difference. This genetic and molecular variation is physiologically manifested in lower ROS activity, lower susceptibility to ROS-inducing agent, faster pathogen clearance and higher stem cell activity in resistant versus susceptible lines. This study provides novel insights into the determinants underlying population-level variability in gut immunocompetence, revealing how relatively minor, but systematic genetic and transcriptional variation can mediate overt physiological differences that determine enteric infection susceptibility.

Background: The incidence, clinical relevance and pathogenesis of single, isolated, varicella-like skin lesions occurring far beyond the primary herpes zoster (HZ)-affected dermatome remain unclear., Objectives: To search prospectively for these satellite lesions in 120 patients with HZ and to correlate their presence with a series of clinical, histological and virological data., Methods: Relevant clinical data were recorded from 109 patients with proven HZ using immunohistochemistry on Tzanck smears. Furthermore, skin biopsies and blood samples were obtained from a subgroup of patients presenting with primary HZ with and without satellite lesions for histology, immunohistology, serology and real-time polymerase chain reaction., Results: This study identified satellite lesions in 21·1% of the patients with HZ. Their presence conveyed a statistically significant relative risk (RR) for severe (RR 3·27, P < 0·001), multidermatomal (RR 10·6, P < 0·001) and multistage HZ (RR 3·30, P < 0·001); systemic signs (RR 2·08, P = 0·0031); immunosuppression (RR 2·38, P = 0·0014) and hospitalization (RR 2·94, P < 0·001). Varicella zoster virus (VZV) viraemia was higher (mean 4075 copies mL(-1) ) in patients with HZ with satellite lesions than in those without (mean 1466 copies mL(-1) ). In contrast to HZ lesions, satellite lesions often presented positive VZV immunostaining in endothelial cells, suggesting a similar pathogenesis to varicella. A limitation of this study is the centre-linked overrepresentation of immunocompromised patients., Conclusions: Total-body examination searching for satellite lesions is a rapid, simple and reliable tool for identifying patients with high-risk HZ., (© 2014 British Association of Dermatologists.)

Gender and immune status can considerably impact on the pharmacokinetics (PK) of macromolecular and small molecule drugs. However, these effects are often not considered in drug development. We aimed to quantitatively evaluate effects of gender and immune status on the PK of PEGylated interferon in frequently used murine models. Chronically cannulated female athymic nude and female and male immunocompetent C57Bl/6J mice (n = 24 in total) received a single intravenous or subcutaneous (s.c.) dose of PEGylated interferon. Serial blood samples were taken for 48 h. Noncompartmental analysis and population PK modeling with covariate analysis were performed to evaluate the data. The PK of PEGylated interferon followed a three compartment disposition model with two sequential compartments for s.c. absorption. Female nude mice had significantly higher plasma clearance than C57Bl/6J mice (0.503 vs. 0.397 mL/h). Male mice had a slower absorption rate constant (0.138 h(-1)) and extent (46.2%) of s.c. absorption than female mice (0.274 in C57Bl/6J and 0.374 h(-1) in nude, 60.8% in both). Thus, gender and immune status significantly impacted on important PK parameters of PEGylated interferon in murine models commonly utilized in drug development. It is critical to take into account these differences when choosing animal models and conducting translational pharmacology research., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Septic arthritis has long been considered an orthopedic emergency. Historically, Neisseria gonorrhoeae and Staphylococcus aureus have been the most common causes of septic arthritis worldwide but in the modern era of biological therapy and extensive use of prosthetic joint replacements, the spectrum of microbiological causes of septic arthritis has widened considerably. There are also new approaches to diagnosis but therapy remains a challenge, with a need for careful consideration of a combined medical and surgical approach in most cases., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Research in immunology has brought great progress in knowledge of inflammatory processes in the last 2 decades, which also has an impact on the upper airways. Our understanding of the pathophysiology of chronic rhinosinusitis developed from a rather mechanistic point of view with a focus on narrow clefts and mucociliary clearance to the appreciation of a complex network of immunological pathways forming the basis of disease. We today differentiate various forms of inflammation, we start to understand complex immune-regulatory networks and the reasons for their failure, and have already developed innovative approaches for therapy for the most severely ill subjects. Due to this new knowledge in inflammation and remodeling processes within mucosal tissue, specifically on the key driving factors, new diagnostic tools and therapeutic approaches for chronic rhinosinusitis have developed; the differentiation of endotypes based on pathophysiological principles will be crucial for the use of innovative therapies, mostly humanized monoclonal antibodies. Several hundred of those antibodies are currently developed for various indications and will impact our speciality as well as pneumology to a great extent., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. Immunosuppression is associated with increased incidence of MCC., Objective: We sought to determine whether solid organ transplant recipients (SOTR) with MCC had decreased progression-free, disease-specific, and overall survival compared with immunocompetent patients., Methods: We conducted a retrospective cohort study examining 8 SOTR with MCC and 89 immunocompetent control subjects. Cox regression models were generated for outcomes of progression, disease-specific death, and death from any cause, adjusted for patient sex, age at diagnosis, and stage at presentation., Results: SOTR had a 4.1-fold increased hazard for progression (95% confidence interval 1.57-10.95, P=.004), a 10.5-fold increased hazard for all-cause mortality (95% confidence interval 3.06-35.98, P<.0001), and an 11.9-fold increased hazard for MCC-specific death (95% confidence interval 2.67-53.08, P=.001), adjusted for sex, age, and stage at presentation. SOTR had decreased 1-year overall survival, 46.8% versus 88.6%, and decreased 1-year MCC-specific survival, 56.3% versus 95.2%., Limitations: This is a single-center study from a tertiary academic care center, and may not be generalizable to all patient populations., Conclusions: SOTR have a significant reduction in overall, MCC-specific, and progression-free survival compared with immunocompetent patients. Further studies will determine whether aggressive treatment may improve outcomes in this high-risk population., (Copyright © 2014 American Academy of Dermatology, Inc. All rights reserved.)

Sex differences in immunity are often observed, with males generally having a weaker immune system than females. However, recent data in a sex-role-reversed species in which females compete to mate with males suggest that sexually competitive females have a weaker immune response. These findings support the hypothesis that sexual dimorphism in immunity has evolved in response to sex-specific fitness returns of investment in traits such as parental investment and longevity, but the scarcity of data in sex-reversed species prevents us from drawing general conclusions. Using an insect species in which males make a large but variable parental investment in their offspring, we use two indicators of immunocompetence to test the hypothesis that sex-biased immunity is determined by differences in parental investment. We found that when the value of paternal investment was experimentally increased, male immune investment became relatively greater than that of females. Thus, in this system, in which the direction of sexual competition is plastic, the direction of sex-biased immunity is also plastic and appears to track relative parental investment., (© 2014 The Author(s) Published by the Royal Society. All rights reserved.)

We studied the effects of early weaning on immunocompetence and parasite resistance in a precocial rodent Acomys cahirinus. We hypothesized that if parasite resistance is energetically expensive and nutritional and immunological support from mothers are necessary for the long-term health of offspring, then early weaned animals would be immunologically weaker and less able to defend themselves against parasites than later weaned animals. We weaned pups at 14, 21 or 28 days after birth and assessed their immunocompetence and resistance against fleas Parapulex chephrenis when they attained adulthood. Immunocompetence was assessed using leukocyte concentration (LC) and a phytohaemagglutinin injection assay (PHA test). To estimate resistance against fleas, we measured performance of fleas via the number of produced eggs and duration of development and resistance to starvation of the flea offspring. We found a significant positive effect of weaning age on the PHA response but not on LC. The effect of age at weaning on flea egg production was manifested in male but not female hosts, with egg production being higher if a host was weaned at 14 than at 28 days. Weaning age of the host did not affect either duration of development or resistance to starvation of fleas produced by mothers fed on these hosts. We conclude that even in relatively precocial mammals, weaning age is an important indicator of future immunological responses and the ability of an animal to resist parasite infestations. Hosts weaned at an earlier age make easier, less-resistant targets for parasite infestations than hosts weaned later in life., (© 2014. Published by The Company of Biologists Ltd.)

Direct ingestion of plant materials has been shown to have immunomodulatory effects on a variety of herbivores. Studies have also shown that compounds ingested indirectly by predators through prey items can affect the general physiology of the ingesting organism. Relatively little data exists, however, concerning the modulation of a predator's immune system via compounds obtained indirectly through prey. In this study, we sought to determine if the immune-stimulating properties of Punica granatum (pomegranate) could be conveyed from a prey organism, Acheta domestica, to a predator, Rhinella marina, through diet specialization. Experimental crickets were fed a diet of agar supplemented with 10 mg/mL of lyophilized, powdered, whole pomegranate while control crickets were fed unadulterated agar. Experimental toads consumed a diet consisting of crickets fed the pomegranate-enriched diet, while control toads consumed a diet consisting of crickets fed the standard agar diet. Blood samples were taken weekly and leukocyte profiles and neutrophil phagocytic activity were determined for all toads over an 8-week period. Complement activity was measured at 6 weeks. Toads fed the pomegranate-enriched diet showed altered leukocyte profiles as evidenced by an increase in circulating eosinophil number and a decrease in the number of circulating lymphocytes, monocytes, and basophils as compared to controls, indicating an immunomodulatory effect of the pomegranate-enhanced diet. These results suggest that pomegranate-derived immunomodulatory compounds can be transferred from prey to predator, and suggests that the flora in the environment where insectivores forage could have a significant effect on the physiology of the animal., (© 2014 Wiley Periodicals, Inc.)

Cryptococcal meningitis is associated with significant morbidity and is rare among immunocompetent patients. Clinical presentation as well as the course of disease is usually indolent which may delay the diagnosis. We present the case of a 52-year-old woman admitted with headaches, vomiting and fatigue for 3 weeks. She was diagnosed with cryptococcal meningitis and treated with antifungal therapy. She was referred for ophthalmological examination presenting with decreased vision in the left eye (OS; count fingers), left relative afferent pupillary defect and bilateral sixth nerve palsy. Funduscopy revealed florid bilateral papilloedema. Cranial MRI showed indirect signs of intracranial hypertension as well as multiple parenchymal lesions and optic nerve sheath enhancement after contrast administration. A ventriculoperitoneal shunt was placed. In spite of the control of intracranial pressure there was a decrease in vision in the right eye (OD) and deterioration of visual fields. Intravenous methylprednisolone was used to reverse optic neuropathy and to prevent OD visual loss., (2014 BMJ Publishing Group Ltd.)

Sturgeon aquaculture has increased considerably worldwide but little is known about their immunological development and competence in early life stages. Culture of larvae is one of the most critical stages in intensive sturgeon farming, often associated with high mortality rates. The objective of this study was to characterize the developmental morphology (light and transmission electron microscopy, LM and TEM) of the meningeal myeloid tissue, spleen and thymus in Atlantic sturgeon (Acipenser oxyrinchus oxyrinchus) from hatching until 5 months old (2895°C·day (dd)). The spleen was first visible on 541 dd larvae LM sections and the other two immune organs in 768 dd samples (approximately 400 and 600 dd after onset of feeding). Generally, younger fish had significantly higher percentages of undifferentiated cells (meningeal myeloid tissue and spleen) and effective adaptive immune competence would not be expected in these fish on the onset of feeding, but further functional immune assessment is needed., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background/aims: There is an increased risk for inflammatory bowel disease (IBD) patients to develop infections due to the use of immunomodulators and biologics. Several infections are preventable by immunizations. This study investigated the knowledge and awareness of Korean gastroenterologists regarding the vaccination of patients with IBD., Methods: A self-reported questionnaire was sent by e-mail to the faculty members of tertiary hospitals. Gastroenterologists were asked ten questions regarding the immunization of patients with IBD. A total of 56 gastroenterologists completed the questionnaire., Results: A majority of gastroenterologists (>60%) had rarely or never recorded an immunization history from their patients with IBD. Moreover, 50% to 70% of the gastroenterologists did not know that live vaccines should be avoided in immunosuppressed patients. The most commonly mentioned resistance to vaccinations was "the lack of concern and knowledge regarding vaccination." Gastroenterologists more frequently asked about the immunization history of influenza, pneumococcal, hepatitis A, and hepatitis B vaccines and recommended these vaccines more often than others., Conclusions: Korean gastroenterologists' awareness and knowledge regarding the vaccination of patients with IBD were very poor. Intensive educational programs on immunization guidelines directed toward gastroenterologists who care for patients with IBD are required to ensure that these patients receive the necessary vaccinations.

Optimal nutrition during infancy is critical not only to support the dramatic growth and development that takes place during the first 12 months following birth but also for establishing a healthy immune response throughout childhood and across the life span. The normative standards for infant feeding and nutrition are breast-feeding and human breast milk. However, in cases in which human breast milk is not available, infant formula is substituted. Providing optimal patient care that results in the best clinical outcomes depends on understanding the unique attributes of the 3 main sources of nutrition for newborns. This state of the science review provides an update on the macronutrient and immunological content of human milk, donor milk, and infant formula and highlights the relevance of these sources of infant nutrition on the development of immune system.

Intimate Partner Violence (IPV) perpetrators use physical and/or psychological abuse to control their partners and achieve a dominant status. As dominance is associated with low disease risk and fast quick illness recovery from an illness, such behaviors may contribute to improving their health at the expense of that of the battered women. Studies with immunological and hormonal parameters have recently revealed that IPV perpetrators present higher general immunocompetence (salivary IgA levels) in response to acute stress, especially during the preparation/anticipation period and when externalizing their anger. Salivary IgA levels have been proved to be increased by hormones, specifically by high testosterone and low cortisol characteristic in IPV perpetrators. Moreover, a high proneness to express anger (defined by high T/C ratio) supposes an increase in self-esteem and mental health. Thus, the use of violence against partners could reinforce their dominant status and, consequently, may serve to indirectly promote IPV perpetrators' immunity.

Migration often is associated with movement away from areas with depleted nutrients or other resources, and yet migration itself is energetically demanding. Migrating Mormon crickets Anabrus simplex (Orthoptera: Tettigoniidae) lack nutrients, and supplementation of deficient nutrients slows migratory movements and enhances specific aspects of their immune systems. Migrants deficient in proteins have less spontaneous phenoloxidase (PO) activity, whereas those deficient in carbohydrates have lower lysozyme-like anti-bacterial titers with a proposed compromise between migratory and anti-bacterial activities. To investigate the relationship between diet, movement, and immunity further, we removed Mormon crickets from a migratory band and offered each cricket one of five diets: high protein, high carbohydrate, equal weight of proteins and carbohydrates (P + C), vitamins only, or water only for 1 h. We then attached a radio, returned each to the migratory band, and recaptured them 18-24 h later. Mormon crickets fed protein moved the furthest, those with only water or only vitamins moved less, and those fed carbohydrates or P + C moved the least. Standard intake trials also indicated that the Mormon crickets were deficient in carbohydrates. Consistent with a previous study, lysozyme-like anti-bacterial activity was greatest in those fed carbohydrates, and there was no difference between those fed water, protein, or P + C. Crickets were removed from the same migratory band and fed one of four diets: high P, high C, P + C, or vitamins only, for 1 h. Then the crickets were held in captivity with water only for 4 or 24 h before blood was drawn. Immunity measures did not differ between times of draw. Diet treatments had no effect on anti-bacterial activity of captive Mormon crickets, whereas total PO was greater in those fed protein. These results support the hypothesis of a direct compromise between migratory and anti-bacterial activities, whereas PO is compromised by low protein independent of migratory activities. We discuss the potential effects of climate on nutritional deficits and susceptibility to different pathogens.

Evolutionary theories of human attraction draw heavily upon nonhuman literature, and currently the Immunocompetence Handicap Hypothesis dominates research into female attraction to male facial masculinity. Although some studies have shown links between masculinity and some measures of health, other data have failed to support the Immunocompetence Hypothesis as applied to human face preferences. Here we summarize that literature and present new data regarding links between masculinity and multiple measures of health condition in human males. Undergraduate males were photographed and their faces were assessed for sexual dimorphism using multiple methods and rated for apparent healthiness and attractiveness. Participants also reported recent health experiences both prior to being photographed and then again 10 weeks later. Although both attractiveness and rated health were associated with better actual health in the past and future (mainly indexed by lower antibiotic use), results were mixed for masculinity. With respect to respiratory illnesses, facial masculinity (assessed using morphometric techniques) was associated with better past health but with worse future health. Possible reasons for the complex and inconsistent findings are discussed and some potentially fruitful avenues of future research are outlined.

Background: The development of neurological complications due to varicella zoster virus (VZV) reactivation is relatively uncommon, particularly in the case of immunocompetent patients. Only a few cases have been described in the literature, most of which involved adult or elderly patients., Clinical Presentation: Two days after his pediatrician had diagnosed herpes zoster and prescribed oral acyclovir 400 mg three times a day, a 14-year-old boy was admitted to our hospital because of mild fever, severe headache, slowness, drowsiness and vomiting. A cerebrospinal fluid examination was performed and showed an increased protein concentration (95 mg/dL), normal glucose level (48 mg/dL; blood glucose level, 76 mg/dL) and lymphocytic pleocytosis (1,400 lymphocytes/μL), and VZV DNA was detected by means of polymerase chain reaction (1,250 copies/mL). The results of immunological screening for HIV, lymphocyte subpopulation counts, serum immunoglobulin and complement (C3 and C4) levels, vaccine responsiveness and lymphocytes stimulation tests were unremarkable. Acyclovir was administered intravenously at a dose of 10 mg/kg three times a day and continued for 10 days. The therapy was highly effective and the patient's clinical condition rapidly improved: fever disappeared after two days, and all of the signs and symptoms of neurological involvement after four days. The skin lesions resolved in about one week, and no pain or dysesthesia was ever reported. Given the favourable evolution of the illness, the child was discharged without further therapy after the 10-day treatment. The findings of a magnetic resonance examination immediately after the discontinuation of the antiviral therapy were normal, and a control examination carried out about four weeks later did not find any sign or symptom of disease., Conclusion: VZV reactivation can also lead to various neurological complications in immunocompetent children. Prompt therapy with acyclovir and the integrity of the immune system are important in conditioning outcome, but other currently unknown factors probably also play a role.

The trade-offs between reproduction and survival or future reproduction represent the costs of reproduction, which are central to the theory of life-history traits evolution. In particular, different stages of the reproductive cycle may be associated with different costs and thus explain the evolution of alternative reproductive strategies. Viviparity (live bearing) has evolved from oviparity (egg laying) several times independently in vertebrates. To better understand these transitions, we aimed to specifically investigate gestation costs in a squamate reptile with a new experimental procedure. We reduced litter size during gestation in the common lizard (Zootoca vivipara) with a hormonal injection of arginine vasotocin. This method is less invasive than a surgical method and does not reduce the number of offspring of future reproductive events. We monitored body mass change, immune response, endurance capacity, thermoregulatory behavior, offspring characteristic at birth, female and offspring survival, female body mass gain after parturition, and offspring growth rate after birth. Maternal treatment did not significantly change the offspring characteristics measured. Thus, litter size reduction did not change offspring development during gestation. For the females, there is evidence that endurance capacity during gestation is modified because of the physical burden of the litter and because of physiological changes. With respect to gestation costs, we did not observe a trade-off between the investment during gestation and females' resources postparturition (female body mass) or survival, but there was a facultative trade-off with the immune response. It will be interesting to replicate this study to increase the robustness of these results and to confirm the effects on the endurance capacity and the immune response. Gestation costs seem to be limited in this species, and they should be studied in more detail to evaluate their influence on the evolution of viviparity.

The conclusions of pairwise meta-analyses of interventions for actinic keratosis (AK) are limited due to the lack of direct comparison between some interventions. Consequently, we performed a network meta-analysis for eight treatments [5-aminolaevulinic acid (ALA)-photodynamic therapy (PDT), cryotherapy, diclofenac 3% in 2·5% hyaluronic acid (DCF/HA), 5-fluorouracil (5-FU) 0·5% or 5·0%, imiquimod (IMI) 5%, ingenol mebutate (IMB) 0·015-0·05%, methyl aminolaevulinate (MAL)-PDT and placebo/vehicle (including placebo-PDT)] to determine their relative efficacies. As part of a prior Cochrane systematic review, different databases and grey literature were searched for randomized controlled trials up to April 2012. The inclusion criteria were parallel-group studies with nonimmunosuppressed participants: (i) reporting 'participant complete clearance' and (ii) comparing at least two of the interventions. Thirty-two publications met the criteria and they included the following number of individual or pooled studies (n) and total number of participants (N) for the different interventions: 5-FU 0·5% (n = 4, N = 169), 5-FU 5·0% (n = 2, N = 44), ALA-PDT (n = 6, N = 739), cryotherapy (n = 2, N = 174), DCF/HA (n = 5, N = 299), IMI (n = 14, N = 1411), IMB (n = 3, N = 560), MAL-PDT (n = 7, N = 557) and placebo (n = 32, N = 2520). Network analyses using a random-effects Bayesian model were carried out with the software ADDIS v1.16.1. The interventions were ranked as follows based on calculated probabilities and odd ratios: 5-FU > ALA-PDT ≈ IMI ≈ IMB ≈ MAL-PDT > cryotherapy > DCF/HA > placebo. This efficacy ranking was obtained based on the current available data on 'participant complete clearance' from randomized controlled trials and the analysis model used. However, several other factors should also be considered when prescribing a treatment for AK., (© 2013 Mediprobe Research Inc BJD © 2013 British Association of Dermatologists.)

Background: Successful cell therapy relies on the identification and mass expansion of functional cells for infusion. Cryopreservation of cells is an inevitable step in most cell therapies which also entails consequences for the frozen cells., Material and Methods: This study assessed the impact of cryopreservation and the widely used protocol for rapid expansion of T lymphocytes. The effects on cell viability, immunocompetence and the impact on apoptotic and immunosuppressive marker expression were analyzed using validated assays., Results and Conclusion: Cryopreservation of lymphocytes during the rapid expansion protocol did not affect cell viability. Lymphocytes that underwent mass expansion or culture in high dose IL-2 were unable to respond to PHA stimulation by intracellular ATP production immediately after thawing (ATP = 16 ± 11 ng/ml). However, their reactivity to PHA was regained within 48 hours of recovery (ATP = 356 ± 61 ng/ml). Analysis of mRNA levels revealed downregulation of TGF-β and IL-10 at all time points. Culture in high dose IL-2 led to upregulation of p73 and BCL-2 mRNA levels while FoxP3 expression was elevated after culture in IL-2 and artificial TCR stimuli. FoxP3 levels decreased after short-term recovery without IL-2 or stimulation. Antigen specificity, as determined by IFNγ secretion, was unaffected by cryopreservation but was completely lost after addition of high dose IL-2 and artificial TCR stimuli. In conclusion, allowing short-time recovery of mass expanded and cryopreserved cells before reinfusion could enhance the outcome of adoptive cell therapy as the cells regain immune competence and specificity.

In most species--from cyanobacteria to humans--genetically encoded circadian clocks have evolved to adapt behavioral and physiological processes to environmental changes brought about by the Earth's rotation. Clock disruption, e. g. by shift work, can lead to circadian misalignment, promoting the development of metabolic, immune and cognitive dysfunction. In mammals, a central circadian pacemaker residing in the suprachiasmatic nuclei of the hypothalamus resets subordinate, but semi-independent cellular clocks in tissues such as liver, kidney, adrenal, and many brain areas. Peripheral clocks regulate various endocrine, metabolic and immune processes, whereas central oscillators modulate basic as well as higher brain functions. For the clinical practice it is of major importance to be aware of these physiological rhythms in order to correctly interpret laboratory data and other disease symptoms. Chronomedical therapies can reduce side effects and increase efficacy by optimizing the timing of treatment or directly affect disease state by restoring internal circadian synchrony., (© Georg Thieme Verlag KG Stuttgart · New York.)

Psychological stress has extreme adverse consequences on health. However, the molecular mechanisms that mediate and accelerate the process of aging due to stress hormone are not well defined. This review has focused on diverse molecular paths that come out in response to chronic psychological stress via releasing of excessive glucocorticoids (GCs), involved in the aging process. GCs suppress transcription of nuclear cell adhesion molecules which impair synaptic plasticity, memory formation, and cognitive ability. Again, GCs promote muscle atrophy by means of motivating ubiquitin proteasome system and can repress muscle protein synthesis by inhibition of PI3-kinase/Akt pathway. GCs also inhibit interleukin-2 synthesis through suppressing T cell receptor signal that leads to loss of T cell activation, proliferation, and B-cell activation. Moreover, GCs increase the expression of collagenase-3, RANK ligand, and colony stimulating factor-1 that induce bone resorption. In general, stress-induced GCs can play causal role for aging and age-related disorders.